PDBsum entry 1orv

Hydrolase

PDB id: 1orv

Contents

Protein chains

728 a.a. *

Ligands

NAG-NAG ×7

NAG-NAG-BMA ×2

NAG ×15

SO4 ×4

Waters ×1468

* Residue conservation analysis

PDB id:

1orv

Name:

Hydrolase

Title:

Crystal structure of porcine dipeptidyl peptidase iv (cd26)

Structure:

Dipeptidyl peptidase iv. Chain: a, b, c, d. Fragment: extracellular domain. Ec: 3.4.14.5

Source:

Sus scrofa. Pig. Organism_taxid: 9823. Other_details: kidney

Biol. unit:

Dimer (from PQS)

Resolution:

1.80Å R-factor: 0.217 R-free: 0.252

Authors:

M.Engel,T.Hoffmann,L.Wagner,M.Wermann,U.Heiser,R.Kiefersauer,R.Huber, W.Bode,H.U.Demuth,H.Brandstetter

Key ref:

M.Engel et al. (2003). The crystal structure of dipeptidyl peptidase IV (CD26) reveals its functional regulation and enzymatic mechanism. Proc Natl Acad Sci U S A, 100, 5063-5068. PubMed id: 12690074 DOI: 10.1073/pnas.0230620100

Date:

16-Mar-03 Release date: 06-May-03

Protein chains

P22411  (DPP4_PIG) -  Dipeptidyl peptidase 4 from Sus scrofa

Seq: 766 a.a.

Struc: 728 a.a.

Enzyme reactions

• Enzyme class: E.C.3.4.14.5 - dipeptidyl-peptidase Iv.
• Reaction: Release of an N-terminal dipeptide, Xaa-Xbb-|-Xcc, from a polypeptide, preferentially when Xbb is Pro, provided Xcc is neither Pro nor hydroxyproline.

DOI no: 10.1073/pnas.0230620100

Proc Natl Acad Sci U S A 100:5063-5068 (2003)

PubMed id: 12690074

The crystal structure of dipeptidyl peptidase IV (CD26) reveals its functional regulation and enzymatic mechanism.

M.Engel, T.Hoffmann, L.Wagner, M.Wermann, U.Heiser, R.Kiefersauer, R.Huber, W.Bode, H.U.Demuth, H.Brandstetter.

ABSTRACT

The membrane-bound glycoprotein dipeptidyl peptidase IV (DP IV, CD26) is a unique multifunctional protein, acting as receptor, binding and proteolytic molecule. We have determined the sequence and 1.8 A crystal structure of native DP IV prepared from porcine kidney. The crystal structure reveals a 2-2-2 symmetric tetrameric assembly which depends on the natively glycosylated beta-propeller blade IV. The crystal structure indicates that tetramerization of DP IV is a key mechanism to regulate its interaction with other components. Each subunit comprises two structural domains, the N-terminal eight-bladed beta-propeller with open Velcro topology and the C-terminal alpha/beta-hydrolase domain. Analogy with the structurally related POP and tricorn protease suggests that substrates access the buried active site through the beta-propeller tunnel while products leave the active site through a separate side exit. A dipeptide mimicking inhibitor complexed to the active site discloses key determinants for substrate recognition, including a Glu-Glu motif that distinguishes DP IV as an aminopeptidase and an oxyanion trap that binds and activates the P(2)-carbonyl oxygen necessary for efficient postproline cleavage. We discuss active and nonactive site-directed inhibition strategies of this pharmaceutical target protein.

Selected figure(s)

Figure 2.
Fig. 2. Soluble DP IV forms a 222 symmetric assembly as a dimer of dimers. The view is along one two-fold axis. Potential glycosylation sites are indicated as gray spheres, and red spheres are the sites modified in our crystal structure. The transmembrane helices and their orientation to the membrane were modeled to illustrate how tetramerization of DP IV can mediate cell-cell contacts. The figures were prepared by using the programs MAIN (25), MOLSCRIPT (55), and RASTER3D (56).

Figure 5.
Fig. 5. Substrate recognition by DP IV. (a) The peptidomimetic inhibitor p-Iodo-Phe-Pyr-CN is covalently bound to active site Ser-630. The accessible surface is indicated and cut open (dark green) for better visibility. (b) Schematic representation of the active site access in tricorn and DP IV.

Figures were selected by an automated process.